Intestinal anti-inflammatory activity of UR-12746, a novel 5-ASA conjugate, on acute and chronic experimental colitis in the rat

Abstract

The present study was undertaken to investigate the intestinal anti-inflammatory effects of UR-12746 on the acute and chronic stages of a trinitrobenzene sulphonic acid (TNBS) experimental model of inflammatory bowel disease (IBD) in the rat. UR-12746 is a novel, locally-acting compound which combines, through an azo bond, 5-aminosalicylic (5-ASA) and UR-12715, a potent platelet activating factor (PAF)-antagonist. UR-12746 oral pretreatment of colitic rats (50 and 100 mg kg(-1)) reduced acute colonic damage when evaluated 2 days after colonic insult. Postreatment for 4 weeks with UR-12746 (50 and 100 mg kg(-1)) resulted in a faster recovery of the damaged colonic mucosa, which was macroscopically significant from the third week. The intestinal anti-inflammatory effect of UR-12746 was associated with a decrease in leukocyte infiltration in the colonic mucosa, which was evidenced both biochemically, by a reduction in myeloperoxidase activity, and histologically, by a lower leukocyte count after morphometric analysis. This effect was higher than that seen with sulphasalazine, when assayed at the same doses and in the same experimental conditions. Several mechanisms can be involved in the beneficial effects showed by UR-12746: inhibition of leukotriene B(4) synthesis in the inflamed colon, improvement of the altered colonic oxidative status, and reduction of colonic interleukin-1beta production. The results suggest that the intestinal anti-inflammatory activity of UR-12746 can be attributed to the additive effects exerted by 5-ASA and UR-12715, the PAF antagonist compound, that are released in the colonic lumen after reduction of the azo bond by the intestinal bacteria.

Figure 1

Structure of UR-12746.

Figure 2

Histological sections of colonic mucosa from colitic rats 48 h after TNBS instillation (acute phase). (a) Non-colitic group; (b) TNBS-control group; (c and d:) UR-12746 treated groups at doses of 50 and 100 mg kg⁻¹, respectively. Original magnification: 100×. Calibration bar=150 μm.

Figure 3

Histological sections of colonic mucosa from colitic rats 4 weeks after TNBS instillation (chronic phase) (a) TNBS-control group: (b and c) UR-12746 treated groups at doses of 50 and 100 mg kg⁻¹, respectively. Original magnification: 100×. Calibration bar=150 μm.

Figure 4

Effects of UR-12746 (UR) and sulphasalazine (SAZ) treatment (50 and 100 mg kg⁻¹) on leukocyte infiltration in colonic tissue in the chronic phase of TNBS colitis. Data are expressed as mean±s.e.mean. ^* P<0.05, ^** P<0.01 vs TNBS control group. All groups differ significantly from the non-colitic group (P<0.01, not shown) except those marked with # (P>0.05).

Figure 5

Effects of UR-12746 (UR) and sulphasalazine (SAZ) treatment (50 and 100 mg kg⁻¹) on colonic myeloperoxidase (MPO) activity in the chronic phase of TNBS colitis. Data are expressed as mean±s.e.mean. ^*P<0.05, ^**P<0.01 vs TNBS control group. All groups differ significantly from the non-colitic group (P<0.01, not shown) except those marked with # (P>0.05).

Figure 6

Effects of UR-12746 (UR) and sulphasalazine (SAZ) treatment (50 and 100 mg kg⁻¹) on colonic glutathione (GSH) contents in the chronic phase of TNBS colitis. Data are expressed as mean±s.e.mean. ^*P<0.05, ^**P<0.01 vs TNBS control group # P<0.05, ## P<0.01 vs non-colitic group.

Figure 7

Effects of UR-12746 (UR) and sulphasalazine (SAZ) treatment (50 and 100 mg kg⁻¹) on colonic malonyldialdehyde (MDA) levels in the chronic phase of TNBS colitis. Data are expressed as mean±s.e.mean. ^*P<0.05, ^**P<0.01 vs TNBS control group. # P<0.05, ## P<0.01 vs. non-colitic group.

Figure 8

Effects of UR-12746 (UR) and sulphasalazine (SAZ) treatment (50 and 100 mg kg⁻¹) on interleukin-1β (IL-1β) levels in the chronic phase of TNBS colitis. Data are expressed as mean±s.e.mean. ^*P<0.05, ^**P<0.01 vs TNBS control group. ## P<0.01 vs non-colitic group.

Figure 9

Effects of UR-12746 (UR) and sulphasalazine (SAZ) treatment (50 and 100 mg kg⁻¹) on leukotrinene B₄ (LTB₄) levels in the chronic phase of TNBS colitis. Data are expressed as mean±s.e.mean. ^*P<0.05, ^**P<0.01 vs TNBS control group. All groups differ significantly from the non-colitic group (P<0.01, not shown) except those marked with # (P>0.05).